Since 1988 the NIMH Genetics Initiative has supported a national resource for the study of bipolar disorder (BP). By 1997 153 multiplex families were assessed, providing cell lines, DNA, and anonymized clinical data. This is now a publicly available resource and analytic results have been published. A second effort commenced in 1998 to ascertain 500 new BP sib pairs and this goal has been exceeded with 523 additional BPI sib pairs ascertained, interviewed, and a DNA sample collected. A genome wide scan has been completed at the Center for Inherited Disease Research (CIDR) on 237 sib pair families and the remaining 309 families was genotyped by CIDR during 2003. This resource, the largest of its kind, has revealed evidence for areas of linkage on chromosomes 6q and 17q. It has also provided confirmation of a locus on chromosome 22q and support for areas on 1p, 10p, 16p, 13q, and 21q. Accumulating linkage data has implicated other chromosomal regions. This extension of the national genetic resource will include a sample of 5000 unrelated BP probands and 2000 parents for case-control, and family-based association studies. Control samples will be obtained through the NIMH Genetics Initiative national resource. Probands and parents will be ascertained and assessed at eleven sites (the ten sites previously participating plus Howard University, which will provide African-American probands). Parental DNAs in a subsample will allow control for ethnic stratification. This sample will be a national resource for fine scale linkage disequilibrium mapping within regions of linkage, as well as candidate gene association studies. In the past year, we have succeeded in identifying, through a combined analysis of this sample and several other family samples, the first genome-wide significant linkages in bipolar disorder (McQueen et al 2005). The strongest linkage, on chromosome 6q, corresponds to a region first implicated in the NIMH Wave 3 families (Dick et al 2003), which has been a major focus of this Unit ever since. Our fine mapping efforts in this region have uncovered a marker in the gene GRIK2, encoding a receptor for the excitatory neurotransmitter glutamate, that shows reproducible association with bipolar disorder in all 4 waves of the Genetics Initiative Sample. Current work is focused on identifying the functional variation in GRIK2 that accounts for this association finding. A major related project, known as the Bipolar Disorder Phenome Project, aims to collate all of the clinical data collected from all 4000+ participants in the Genetics Initiative study that have been enrolled since 1992. So far we have compiled and verified data on over 2000 variables, accounting for changes in the collection instruments and diagnostic criteria over the last 13 years. This database will become a major resource for future genetic and other biological studies of bipolar disorder.